CMA: Network plasticity in acquired epileptogenesis

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Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and a major source of disability in the veteran population as it is frequently caused by war-time head injuries. More than 1/3 of TLE patients do not respond to anticonvulsant medications and many are not candidates for epilepsy surgery. Therefore, new treatments are needed to prevent the development of epilepsy after the initial insult. Yet, the mechanisms that lead to the development of epilepsy during the period directly after status epilepticus (SE) are still poorly understood. A deep and precise understanding of these mechanisms is critical for development of interventions that can treat temporal epilepsy without the side-effects of medications and potential disability from large surgical resections. To determine the network dynamic changes in specific cell types during the earliest period after SE, we have developed a miniaturized microscope that is completely integrated with a high channel extracellular electrophysiology recording device (E-Scope). We hypothesize that hypersynchronous firing of parvalbumin positive (PV+) and progressive decreased engagement of somatostatin+ (SOM+) interneurons emerge during the epileptogenic period after the insult. We also hypothesize that these pathological circuit dynamics in both excitatory and inhibitory neurons will be readily observed during 200-400 Hz high frequency oscillations (HFOs) have been shown to be a biomarker for hyper-excitable epileptic circuit. In Aim 1 we will measure how PV+ and SOM+ neurons become activated during pathological fast ripples and physiological sharp-wave ripples through the epileptogenic period. In Aim 2, we will measure the precision of spatial coding by excitatory neurons and the reactivation of ensembles during physiological sharp-wave ripples and pathological fast ripples through the epileptogenic period. This information will be critical for identifying the cell specific targets for interventions to prevent epileptogenesis. Overall Strategy: The overall goal of our collaborative merit proposal is to determine the key changes in hippocampal and neocortical circuitry that promotes the development of epilepsy and cognitive dysfunction after the initial insult. Aims of Other Proposals: 1. Wasterlain will use immunocytochemical techniques, including EM immunocytochemistry, to quantify changes in the GABA receptor expression at the synapse and in the peri-synaptic space. 2. Naylor will use in-vitro slice patch clamp recordings, optogenetics, and computational modeling to understand how the functional connectivity of different interneuron types changes during this key period. 3. Smirnakis will use a combination of electrophysiological techniques and in-vivo mesoscopic two-photon calcium imaging to track the activity patterns of neocortical neurons during this period, to understand how hippocampal-cortical communication changes and drives the development of epilepsy. All studies are independent, yet deeply inform each other, as a multi- dimensional understanding will be key for making progress in this highly complex and disabling disorder.